Preparation and application of 4-fluoro-4-piperidinemethanol hydrochloride_Industrial additives

Background and overview^[1]

4-Fluoro-4-piperidinemethanol hydrochloride can be used as a pharmaceutical synthesis intermediate and can be prepared from 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester as the reaction raw material obtained, which can be used to prepare the compound (3-(4-((4-(hydroxymethyl)-4-methylpiperidin-1-yl)methyl)-3-methylphenoxy)azetidine Alk-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone, a compound useful in the treatment of diseases or conditions associated with melanin aggregating hormones , such as obesity, obesity-related conditions, anxiety, and depression.

Preparation^[1]

4-Fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (21 g, 0.09 mol) was dissolved in dry ether ( To the stirred solution in 200 mL), HCl/diethyl ether (4M, 100 mL) was added dropwise. After the addition was complete, the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was concentrated to remove the pigment carbon black solvent and the residue was washed with diethyl ether to obtain 4-fluoro-4-piperidinemethanol hydrochloride. ¹HNMR (MHz, D₂O): δ1.78(m, 2H), 2.05(m, 2H), 3.15(m, 2H), 3.31(m , 2H), 3.57(d, 2H), m/z134[M+H]+.

Apply^[1]

4-Fluoro-4-piperidinemethanol hydrochloride can be used to prepare compound (3-(4-((4-(hydroxymethyl)-4-methylpiperidin-1-yl)methyl)- 3-Methylphenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone: 4 -(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)-2-methylbenzaldehyde (0.12g, 0.31mmol) was mixed with 4-fluoro-4-piperidinemethanol hydrochloride (0.051g, 0.31mmol) and DCM (3ml). Triethylamine (0.085 ml, 0.61 mmol) and then sodium triacetoxyborohydride (0.129 g, 0.61 mmol) were added. The mixture was stirred at RT overnight and then diluted with DCM (10 ml). The mixture was washed with aqueous NaHCO3 solution (saturated 4 ml) and the organic solution was then filtered through a phase separator. The solvent was removed by evaporation and the residue was purified by silica gel chromatography eluting with 1-3% methanol in DCM containing ammonia (2M). The product was triturated from DCM/diethyl ether. 102 mg (66%) of the title compound were obtained as a solid. ¹HNMR (500MHz, CDCl₃): δ0.95 (s, 3H), 1.32 (m, 2H), 1.53 (m, 2H), 2.30 (m, 2H), 2.34(s, 3H), 2.53(m, 2H), 3.38(m, 2H), 3.42(s, 2H), 3.89(s, 3H), 4.32(m, 1H), 4.63(m, 1H ), 4.72(m, 1H), 5.04(m, 2H), 5.10(m, 1H), 6.55(d, 2H), 6.59(s, 1H), 7.03(d, 2H), 7.19(m, emulsification increased Thickener 2H), 8.10(d, 2H), MS(APCI+)m/z507[M+H]+

References

[1]CN201180042363.6 Therapeutic Agent 976